Molecular dynamics of mismatch detection-How MutS uses indirect readout to find errors in DNA

Area of Science:

• Molecular Biology
• Genomics
• Biophysics

Background:

• The mismatch repair protein MutS is crucial for maintaining genomic integrity by detecting and initiating the repair of DNA basepairing errors.
• Previous studies using single-molecule techniques and crystal structures revealed MutS's scanning behavior and its characteristic mismatch-recognition complex, but the atomic-level details of the search process remained unclear.

Purpose of the Study:

• To elucidate the atomic-level structural dynamics of the MutS search mechanism for DNA mismatches.
• To understand how MutS transitions from scanning large stretches of DNA to recognizing rare basepairing errors.

Main Methods:

• 10 μs all-atom molecular dynamics simulations were performed on Thermus aquaticus MutS bound to both homoduplex and T-bulge DNA.
• Analysis focused on the interactions between MutS and DNA, including shape, conformational flexibility, and local deformability.

Main Results:

• MutS employs a multistep mechanism to inspect DNA over two helical turns by assessing its shape via sugar-phosphate backbone contacts.
• Conformational flexibility is evaluated through large-scale clamp domain motions, while local deformability is probed by basepair destabilizing contacts.
• MutS localizes potential targets through indirect readout, favoring the bending of mismatched DNA due to lower energetic costs and identifying sites that deform easily.

Conclusions:

• MutS utilizes a combination of shape, flexibility, and deformability sensing to efficiently scan DNA and identify mismatches.
• The Phe-X-Glu motif in MutS plays a role in locking the mismatch-recognition complex to initiate DNA repair.